Cocaine-induced paranoia and psychotic symptoms (CIPPS) are associated with violence and greater morbidity in cocaine users. Since the phenotype appears only after chronic cocaine use, CIPPS provides a direct human example of cocaine-induced sensitization, an understanding of which is critical to addiction science. Genetic factors are important in CIPPS. CIPPS symptoms comprise a relatively homogeneous phenotypic spectrum. Thus, users who develop CIPPS, and those who do not, each represent more homogeneous groups of cocaine users, in whom genetic investigations are more likely to be fruitful than in those merely meeting dependence criteria. To examine the genetics of CIPPS, this work will: (1) Collect DNA samples from unrelated cocaine-using subjects in whom the CIPPS phenotype has been thoroughly evaluated, and from family trios containing probands carefully assessed for CIPPS. (2) Replicate and extend previous findings from this laboratory on the relationship of allelic variation at genes expressed in catecholamine neurons and CIPPS. (3) Determine relationships between genotypes, biochemical phenotypes, and behavioral phenotypes in African- and European-Americans. (4) Use methods previously developed for idiopathic psychoses to evaluate psychotic realm experiences and related psychological phenomena in abstinent cocaine users. Important strengths of the proposed work are (1) Development of unique DNA resources Suitable for extensive future study, including a first-of-its-kind family collection. (2) A focus on candidate genes supported by previous positive results and neurobiological considerations. (3) Use of haplotypes as well as single genotypes in genetic analysis. (4) Application of well-validated measures of psychosis: the Bell Object Relations and Reality Testing Inventory, the Scale for Assessment of Positive Symptoms, as well as the Cocaine Experience Questionnaire. (5) The use of a repeated measures design in phenotypic assessment. (5) Possible identification of phenotypes that do not depend on cocaine intoxication for expression. This program of research will improve our understanding of the genetics underlying human brain responses to chronic cocaine exposure, thus leading to better diagnosis and treatments for cocaine dependence and other addictive disorders.